Cognitive deficits are an intrinsic part of schizophrenia, occurring independently of positive symptoms, and often persisting even when psychotic symptoms of schizophrenia have been successfully treated. Cognitive functioning is moderately to severely impaired in patients with schizophrenia and is typically present even in the prodromal phase of the disorder, in young drug-nave patients. The deficits are in the domain of executive function largely controlled by the prefrontal cortex (PFC). However, there is only a fragmentary understanding of biochemical dysfunctions in brain that leads to cognitive impairment in schizophrenia. Furthermore, even though atypical antipsychotic drugs can improve certain aspects of cognition, many patients do not achieve remission. Therefore, the development of new therapeutic drugs for cognitive impairment remains imperative. However, the design of new agents for treating cognitive deficits in schizophrenia is hampered by not knowing how the more successful antipsychotic drugs exert their benefit on cognitive function. The goals of the application are to understand the biochemical and synaptic changes in PFC that underlie schizophrenia-like cognitive deficits and identify the beneficial alterations produce by drugs that have demonstrated efficacy in combating these symptoms. These goals will be addressed using non-human primate models that have face, construct and predictive validity for the cognitive deficits of schizophrenia, together with the sex bias that characterizes the risk for schizophrenia. Our hypothesis is that dopamine, brain derived neurotrophic factor (BDNF) and estradiol are important factors that interact in the PFC to modify excitatory spine synapses on dendrites of pyramidal neurons, which in turn critically modulates executive function. This project will use a novel developmental phencyclidine (PCP) model and an adult primate PCP model that have resonance to the dopamine, glutamate and GABA hypotheses of schizophrenia, in addition to being relevant to the theories of developmental origins for the illness. The application has 3 specific aims: 1) Identify to what extent estradiol contributes to resilience of the peri-adolescent monkey PFC to the detrimental biochemical, synaptic and cognitive effects of PCP, 2) Identify the potential of local over-expression of BDNF to initiate recovery of excitatory spine synapses from the impact of PCP on primate PFC, and 3) Identify biochemical, synaptic and cognitive consequences of acute and repeated novel atypical antipsychotic drug administration in PFC of PCP-exposed monkeys. This current project contains refinement of previous theoretical concepts and approaches, and tests the impact of new interventions, utilizing improvements in current methodology. This work is expected to lead to new strategies in treating cognitive deficits in schizophrenia, which is the prime driver of significant disabilities in occupational, social, and economic functioning in patients, and imposes a heavy emotional burden on the family and an economic toll on the healthcare system.